Cardiovascular disease, including diseases of the heart and its blood vessels, is the leading cause of death in the United States (www.cdc.gov/heartdisease/facts.htm). A variety of common diseases can impair blood flow to the heart and/or cardiac function (i.e., the ability of heart muscles to pump blood from the heart chambers). Notably, atherosclerosis is the most common disease of the blood vessels of the heart and a major cause of death in the U.S. Many types of cancer drugs are associated with cardiovascular toxicity involving inflammation of the heart and/or its blood vessels. Numerous other medical conditions are associated with impaired cardiac blood flow and/or cardiac function. Non-invasive medical imaging is the standard-of-care in the diagnosis and evaluation of impaired cardiac blood flow and/or cardiac function.
Standard clinical cardiac imaging modalities include nuclear imaging with specific labeled compounds for PET and SPECT (radiotracers); echocardiography; magnetic resonance imaging; and X-ray computed tomography with intravenous contrast material. For nuclear imaging, standard radiotracers include SPECT agents for evaluating cardiac blood flow (e.g., thallium-201; and technetium 99m-labeled sestamibi or tetrofosmin); PET agents for evaluation cardiac blood flow (e.g., nitrogen-13 ammonia; rubidium-82) and myocardial viability (e.g., fluorine-18 fluorodeoxyglucose); and SPECT and PET agents for evaluating cardiac function (e.g., technetium 99m-labeled red blood cells, as well as the aforementioned SPECT and PET tracers).
Targeted imaging for targeted therapy—using radiolabeled forms of targeted therapeutic agents for PET imaging—is much advocated for the future of medical imaging & drug development, by the National Cancer Institute and others. (National Cancer Institute, U.S. National Institutes of Health. A workshop regarding what in-vivo molecular imaging probes are needed to support future translational studies in cancer therapeutics. Paper presented at: Strategies for Imaging Priority Targets, 2002; Frankfurt, Germany; Weber W A, Czernin J, Phelps M E, Herschman H R. Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs. Nat Clin Pract Oncol. 2008; 5(1):44-54; Workman P, Aboagye E O, Chung Y L, Griffiths J R, Hart R, Leach M O, Maxwell R J, McSheehy P M, Price P M, Zweit J. Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst. 2006; 98(9):580-598; Workman P, Burrows F, Neckers L, Rosen N. Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress Ann N Y Acad Sci. 2007; 1113:202-216). The unique potential of PET microdose studies in development of drugs as therapeutic and/or diagnostic imaging agents is recognized by the U.S. F.D.A and others. A review of published PET micro-dosing studies is provided by Wagner et al (Wagner C C, Müller M, Lappin G, Langer O. Positron emission tomography for use in microdosing studies. Curr Opin Drug Discov Devel. 2008 January; 11(1):104-10).
Each of the PET and SPECT tracers demonstrates specific limitations in their usefulness. Notably, SPECT imaging has inferior spatial resolution and sensitivity for detecting tracer in vivo, compared to PET imaging. As a result, PET imaging is better able to detect smaller areas of blood flow obstruction, in the heart; and PET imaging is better able to evaluate the wall motions (blood pumping/cardiac output function) of the heart, where the pumping function of the heart may be dysfunctional due to blood flow obstruction causing wall dysfunction or other causes. Exemplary limitations of standard cardiac PET include:    (A) PET technology is not yet accessible to all medical centers, particularly outside the U.S;    (B) certain PET tracers with short radioisotope half-lives (e.g., nitrogen-13 ammonia) are only available to medical centers with on-site cyclotrons (uncommon even inside the U.S.); and    (C) because of their short half-lives, current PET cardiac blood-flow tracers can only be administered to patients receiving cardiac stress induced by a pharmacologic agent (e.g., adenosine), although physical exercise (e.g., treadmill) is the preferred method of inducing cardiac stress. Clinicians obtain important information from this physical exercise-induced stress, including cardiopulmonary performance data and electrocardiographic (EKG) data that are key in diagnosis of coronary artery disease and cardiac dysfunction and for determining patient prognosis. Because this cardiopulmonary and exercise-EKG information is so vital, cardiac imaging using SPECT tracers and physical exercise is often preferred to PET imaging (during pharmacological stress) for detection of cardiac disease, despite the superior imaging qualities of PET technology. These and other current clinical imaging modalities are limited in their abilities to evaluate cardiac blood flow and function, which may be impaired by a variety of medical conditions. In view of the extraordinary diagnostic value of cardiac imaging and the shortcomings of the technologies discussed above, there is a need for novel and improved methodologies for cardiac imaging.